Nextgenerationimmunomodulation:targetingspecificsoftheimmune
response
EmmanuelleWaubant,MD,PhDProfessorofNeurology
UCSFFebruary23,2017
Outline
• Possibletargets• Ongoingphase3trials• Ongoingphase2trials• Ongoingphase1trials
Extravasation
astrocytes BRAIN TISSUE
M Y E L I Noligodendrocyte
B cell
Rolling Adhesion
α4 IntegrinVCAM LFA-1
ICAM
B L O O D F L O W
LUMEN OF VENULE
B A S A L L A M I N A
Circulation
Activated T cellProteases (MMPs)
Antigen presenting cell(astrocyte or microglial cell)
Activated microglia/macrophages
IFN-γ, IL-2
Cytokines andchemokines
T CELL REACTIVATION
Activated Macrophage
AutoantibodiesComplement
IL-1, IL-12,chemokines
AXONAL DAMAGE
excess glutamate
GluRProteasesTNF-α
O2•-
NO•
CourtesyofDrs Baranzini andHauser
Treatmentstrategiestargetinginflammation• TargetingS1P1:newgenerationagents• Targetingadhesionmolecules:oralalpha4integrinantagonist(firategrast)• TargetingBcells:CD20,CD19,atacicept• TargetingtheTh17pathway• Inductiontherapy:autologoushematopoieticstemcelltransplant• Inducinganergy withpeptides/TCRpeptides/vaccine• TargetinghumanretrovirusHERV(IgG4againstMRSV-Env)• Targetingmacrophage/microgliaactivation throughthemetabolicsyndrome
andperoxisomeproliferator–activatedreceptorγ (PPARγ)• Dietaryintervention:
– caloricrestriction– lowfatdiet
• Immunemodulationwith:– estriol– vitaminD– mesenchymal stemcells– parasiticbasedapproach– microbiota transplant/probiotic
HormonaltherapyPhase3RCTestrioltrialasanadd-onto
GA
Voskhul 2016
PrimaryEndPoint:
confirmedrelapseatmonth24
Voskhul 2016
Estriolgroup(n=82)
Placebogroup(n=76)
Estriolgroupvsplacebogroup pvalue
At24monthsConfirmed relapse
Annualised relapserate(95%CI) 0·25(0·17–0·37) 0·37(0·25–0·53) 0·63(0·37–1·05)* 0·077
Probability offirstrelapse(95%CI)
33·3%(23·8–45·4)†
42·9%(32·1–55·5)† 0·63%(0·36–1·09)¶ 0·096
RelapseeventAnnualised relapserate(95%CI) 0·32(0·22–0·46) 0·46(0·32–0·65) 0·65(0·39–1·08)* 0·098
Probability offirstrelapseevent(95%CI)
40·5%(30·0–53·0)†
46·9%(35·9–59·3)† 0·70%(0·42–1·17)¶ 0·179
At12monthsConfirmed relapse
Annualised relapserate(95%CI) 0·25(0·16–0·40) 0·48(0·33–0·69) 0·49(0·28–0·88)* 0·016
Probability offirstrelapse(95%CI)
22·8%(15·0–33·7)†
33·1%(23·5–45·2)† 0·58%(0·31–1·10)¶ 0·095
RelapseeventAnnualised relapserate(95%CI) 0·33(0·22–0·50) 0·61(0·44–0·84) 0·52(0·31–0·86)* 0·012
Probability offirstrelapseevent(95%CI)
30·7%(21·7–42·3)†
40·3%(30·0–52·7)† 0·65%(0·37–1·14)¶ 0·131
Voskhul 2016
Ongoingphase3trialsinRRMS
• VitaminD3vs.placebo:– asanadd-ontoGA(VIDAMS)– asanadd-ontoIFNB(SOLAR)– inCIS(Australia)
• Open-labelofALKS8700(monomethyl fumarate,Alkermes Inc.)
• Ofatumumab vs.teriflunomide• Ponesimod vs.teriflunomide• Siponimod
VitaminD:MOA
• Immuneeffects– Increasesexpressionofanti-inflammatorycytokines(IL-4,IL-10,TFGb)
– Inhibitsexpressionofpro-inflammatorycytokines(IL-12,IL-17,IFNg,andTNFa)
– ModulatesThelpercells– Inhibitspro-inflammatoryTh17cells
• Decreasedriskofinfections
VitaminDtoAmeliorateMS(VIDAMS)Trial
PI: Mowry (National MS Society)
SOLARSupplementationofVigantOL®OilversusPlaceboasAdd-oninPatientswithRelapsingRemittingMS
receivingRebif®treatment
• Studydesignmodified:– 229patientsenrolled,vitaminD314,000IU/dvs.placebo(1:1)
– Durationreducedto48weeks– PrimaryendpointchangedtoNoEvidenceofDisease(norelapses,noEDSSchange,nonewenhancinglesions,nonew/enlargingT2lesions)
CourtesyofDr.Mowry
SOLAR:Results
• NomeaningfuldifferenceinratesofNEDA(p=0.91)
• ARR0.28invitaminDgroupversus0.41inplacebogroup(p=0.17)
• VitaminD-treatedgroupwaslesslikelytohavenew/enhancinglesions(1.09versus1.49,p=0.005)
From ECTRIMS 2016 slidesCourtesyofDr.Mowry
Ongoingphase2trials• GNbAC1(IgG4againstMRSV-En,envelopeproteinofhumanretrovirusHERV-W:CHANGE-MS,260patients)
• Amiselimod:S1Preceptormodulator(Biogen)• Bruton tyrosin kinase(BTK)inhibitorM2951vs placebovs dimethylfumarate (EMDSerono):BTKimportantindevelopment/functionofBcellsandmacrophages
• Open-labelofTMP001(tarenflurbil)inRRMS(selectivebetaamyloidlowering:modulateγ secretase andNF-KBpathway)
• LowdoseIL-2vs.placeboinrelapsingMS
Bcelltargeting:MOA
• Anti-CD20• Anti-CD19:inebilizumab• Other:atacicept (recombinantfusionproteinbindingBLyS andAPRILwhichareimportantBcellsignals)
Mancardi, Neurology, 2015
JAMA Neurology, 2015
Event-free survival: 78.4% (90% CI, 60.1%-89.0%) at 3 years.
!
- HSCTstopsrelapses- Nocontrolgroup
CanadianBMTStudy:EDSSandbrainatrophy
!
%changeinbrainvolume
!
%patientswithworseningdisability
Atkins, Freedman et al Lancet, 2016 MSSC-RFCourtesy of Dr Bar-Or
Th1
(IFNγ)
Th17 (IL-17)
29.4 6.9
5.458.4
41.2 1.8
3.153.9
freq
uency(%
)relativ
etobaseline
0
50
100
150
p=0.
012
p=0.
020
p=0.
022
Decreased Th17 (but not Th1) responses following HSCT
Darlington et al, Ann Neurol, 2013Courtesy of Dr Bar-Or
Pre-BMT
Post-BMT
Zou W, Restifo, N. Nat Rev Immunol 10: 248–256 (2010).
TargetingtheTh17pathway:MOA
TargetingtheTh17pathway:phase2• Ustekinumab RCT(againstIL-12/23p40criticalinmaintenanceofTh17cells):noreductioninnewGd+lesionsor#relapses
• Secukinumab (AIN457,againstIL-17A)fullyhumanMABapprovedforpsoriasisgivenIV10mg/kg:RCTproof-of-conceptvs.placeboover24weeks
• CJM112(fullyhumanMABagainstIL-17A,Novartis)givenmonthlySCvs.fingolimod pending(PEPcumulativenumberofnewGd+atmonths4,5and6):360subjects(1:1:1)
• ACEinhibitor:lisinopril asanadjunctivetreatment(NCAT,Dr.Lublin,pending)
Segal2008,Havrdova 2016,Weindl ECTRIMS2016
Secukinumab phase2:PEP
Havrdova 2016
73RRMSrandomized1:1
PEP:-49%cumulative#combineduniqueactivelesions (p=0.087)and-67%cumulative#newGd+(p=0.003) insecukinumab group;
SEP:ARRdecreasedby43%inthesecukinumab group (p>0.05)
Mild/moderate infectionsmorefrequent37%vs 23%
Serumdefensin-2(downstreammarkerofIL-17)
Havrdova 2016
Antigen-specific (tolerizing) strategies:Peptide-based approaches (APL, MBP82-98… b-crystalin)
Route: Oral Tolerance; IV
DNA Vaccines: Dendritic Cell Vaccines
Antigen-Coupled Presentation
Autoreactive T-cell vaccination
T Cell Receptor EngineeringAdoptive Transfer Immunotherapy
Enhancing Regulatory T Cell FunctionEnhancing Regulatory B Cell Function
Anti-Idiotypic NetworksTarget-Competitive Antibody in Tolerization
CourtesyofDr.Bar-Or
Phase1studies
• NeuroVax (enhancesFOXP3+Tregs)TCRpeptidevaccine
• Tolerogenic dendriticcells(TOLERVIT-MS):autologousdendriticcellstreatedwithvitaminD3andmyelinpeptides
• ABT555inrelapsingMSasanadd-ontoGA(AbbVie,axonregenerationanddecreasedmicroglialactivation):antiRMAantibody(repulsiveguidancemolecule)
Trzaska.MolecMedReports1:307,2008CourtesyofDr Cohen
Inaddition,MSCscantrafficfromblood intoinflamedor
injured tissue
Mesenchymal stemcells:MOA
MSC Treatment of Multiple Sclerosis
Reference Indication Participants MSC Source
Cohen submitted RR,SPMS 24 Autologous culture-expandedBMMSCs administeredIV
Connick 2012 SPMS 10 Autologous culture-expandedBMMSCs administeredIV
Karussis 2010 RR, SP,PPMS 15 Autologous culture-expandedBMMSCs administeredIVand IT
Liang2009 PPMS 1 Allogeneicumbilical cordMSCsadministeredIVandITafterCTX
Llufriu 2014 RRMS 9 Autologous culture-expandedBMMSCs administeredIV
Mohyeddin Bonad 2007 Treatment-refractoryMS 10 Autologous culture-expandedBMMSCs administeredIT
Rice 2010 Chronic MS 6 FreshBMcellsenrichedforMSCs
Riordan2009 Treatment-refractoryMS 3 Autologous non-expanded adiposeMSCs
Yamout 2010 SPMS 10 Autologous culture-expandedBMMSCs administeredIT
Phase1TrialofAutologousMSCTransplantationinMS
StudyPopulation 24participantsRRorSP/PRMS(∼12each)EDSS3.0-6.5Activediseaseinprior24monthsAfferentvisualsysteminvolvement
Treatment SingleIVinfusionof1-2x106/kgautologousculture-expandedbone-marrow-derivedMSCs
Follow-up 2monthspre- and6monthspost-treatment
Primaryoutcome Feasibility,andinfusion-relatedsafetyandtolerabilityover1month
CourtesyofDrJeffCohen
DietasaDMT?
• Directeffectsoninflammation
• Impactingcellmetabolismandabilitytodealwithdamage
• Alteringthegutmicrobiota
• Reducingtheoccurrenceofotherillnesses
• OthermechanismsCourtesyofDr.Mowry
ImpactofCalorieRestrictioninEAE
• Restrictingcaloriesorfastingpriortodiseaseinduction:àLowerriskofdiseaseàLesssevereEAEà ReducedproinflammatoryleptinàMayimprovecellenergymetabolism
Piccio 2008, Sanna 2003, Esquifino 2007,Galgani 2010
CourtesyofDr Mowry
Fig.1
Multiple Sclerosis and Related Disorders 2016 9, 80-90DOI: (10.1016/j.msard.2016.07.001) Copyright © 2016 Terms and Conditions
LowfatdietOHSUtrial
Yadav 2016CourtesyofDr Yadav
Fig.2
Multiple Sclerosis and Related Disorders 2016 9, 80-90DOI: (10.1016/j.msard.2016.07.001) Copyright © 2016 Terms and Conditions
Yadav 2016CourtesyofDr Yadav
Day 0 Day 15 Month 3 Month 6
Acute IF phase
§ Control: iv steroids + regular diet § IF: iv steroids +IF
Chronic IF phase All subjects on IF
Clinicalevaluation Blood/serumsample Stoolsample
Calorierestriction(CR)pilotstudyinrelapsingMSpatientsatWashU
• CRisachievedbyIntermittentFasting(IF)
• Sixteenpatientshavebeenenrolled
CourtesyofDrLauraPiccio
ATAC-MSStudyAlteringtheTimingandAmountofCaloriesinMS
Normalcalorieamount
Normalcalories5days/week;25%oftypicalcalories2days/week
Modestcaloriereductioneachday(~78%)
36 eligible people with MS
Courtesy of Dr MowrySponsored by NMSS (Harry Weaver Award)
Phase 1: 8 weeks Phase 2: 40 weeks
Targetingthemetabolicsyndrome
• 50obesepatientswithRRMSandmetabolicsyndrome(hyperinsulinemiaorhyperglycemiaandwaistcircum 94cmormore,dyslipidemiaorHDL,orHBP)
• Openlabel:– 20metformin,– 10pioglitazone,– 20notreatment
• 75-80%onDMTatbaseline,mostlyIFNB• BrainMRIevery6months
Negrotto 2016
Date of download: 1/13/2017 Copyright © 2017 American Medical Association. All rights reserved.
From: Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis
Negrotto et al JAMA Neurol. 2016;73(5):520-528. doi:10.1001/jamaneurol.2015.4807
Disease Activity as Measured by Magnetic Resonance Imaging A, Both metformin hydrochloride and pioglitazone hydrochloride were associated with a significant decrease in the number of new or enlarging T2 lesions in comparison with lesions observed 2 years earlier, and with the control group not receiving metformin or pioglitazone. B, Both metformin and pioglitazone were associated with a significant decrease in the number of gadolinium diethylenetriamine penta-acetic acid (Gd)–enhancing lesions in comparison with lesions observed 2 years earlier, and with the control group not receiving metformin or pioglitazone.
Parasitic-based therapy• Helminths induce a Th2 bias• Trichuris suis ova (TSO) (porcine whipworm) in 15
subjects with early RRMS• PEP:
– 1) safety/tolerability of TSO – 2) changes in #Gd+ on monthly brain MRI
Courtesy of Dr. Fleming
MRI Results
Courtesy of Dr. Fleming
Conclusions
• Diversetargetsandstrategiestoaddressinflammation
• Mostnoveltherapeuticstrategiesareinphase1and2trials